Peripheral arterial disease

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

All patients, regardless of their symptoms, should have aggressive risk factor modification including management of blood pressure, lipids, and diabetes; smoking cessation; and diet and weight control.[1][2][53]

Patients with mild-to-moderate claudication should be advised to keep walking, and people who are fit enough should be encouraged to enrol in a structured exercise program.[30] [ ]

Antiplatelet therapy (e.g., aspirin or clopidogrel) and high-intensity statin therapy are recommended for all patients with symptomatic peripheral arterial disease (PAD).[2] Use of low-dose rivaroxaban (a direct oral anticoagulant [DOAC]) combined with low-dose aspirin reduces ischemic events compared with use of aspirin alone, and is recommended as a treatment option for selected patients with symptomatic PAD; however, this combination is associated with a higher risk of major bleeding.[1][2][54]

Evidence to guide management of patients with asymptomatic PAD is lacking but single antiplatelet therapy should be considered based on the increased cardiovascular risk in this population, together with risk factor modification and careful management of comorbidities.[2]

Acute limb ischemia

Acute limb ischemia is a medical emergency.[2] Patients who have sudden decrease in limb perfusion with threatened tissue viability require urgent history and physical examination to determine symptom onset. They need rapid assessment by a vascular surgeon with a view to restoring arterial blood flow as soon as possible.[2] Emergency vascular study assessment should be performed with ankle-brachial index or duplex ultrasound.

Once the diagnosis is established, patients should be started on systemic anticoagulation with unfractionated heparin, unless contraindicated, together with appropriate analgesia.[1][2] For acute ischemic pain, acetaminophen and an opioid (weak or strong) are recommended depending on the severity of pain.[45][55]

Etiologies of acute limb ischemia include embolic, progressive PAD with in situ thrombosis, bypass graft thrombosis, arterial trauma, popliteal cyst or entrapment, hypercoagulable state, or phlegmasia cerulea dolens.

Nonviable limb:

These patients will have signs of tissue loss, nerve damage, and sensory loss and will require amputation.

Viable limb:

These patients will have no significant tissue loss, nerve damage, or significant sensory loss.
Patients should have arterial anatomy defined and undergo revascularization.
Options for revascularization include: percutaneous catheter-directed thrombolytic therapy; percutaneous mechanical thrombus extraction or thrombo-aspiration (with or without thrombolysis); and surgical thrombectomy, bypass, and/or arterial repair.[1] Endovascular therapy is often preferred, especially in patients with severe comorbidities.[1]
Evidence suggests that intra-arterial thrombolytic therapy is as effective as surgery and it has become the modality of choice, with consideration of additional endovascular therapies as required (e.g., for definitive treatment of any underlying culprit lesion).[2] Thrombolytic agents include alteplase, reteplase, and tenecteplase.[56] Although there are several comparative studies, no single thrombolytic agent or regimen has emerged as the treatment of choice.[57][58] Streptokinase is no longer used due to lower efficacy, increased bleeding rate, and antigenicity issues.

Factors influencing choice of revascularization strategy include the presence of a neurologic deficit, duration of ischemia, its localization and patient-specific anatomy, comorbidities, type of conduit (artery or graft), risks related to treatment, and local resource availability.[1][2] [ ]

Claudication (not lifestyle-limiting)

Patients with mild-to-moderate claudication should be advised to keep walking.[30] [ ]

For patients with claudication or any other degree of established PAD, antiplatelet therapy with or without antithrombotic therapy (aspirin alone or clopidogrel alone, or low-dose rivaroxaban combined with low-dose aspirin in selected patients with low bleeding risk) is recommended to reduce risk of myocardial infarction, stroke, and vascular death.[2]

Follow-up visits, at least annually, are required to monitor development of coronary, cerebrovascular, or leg ischemic symptoms.[2]

Claudication (lifestyle-limiting)

Patients with lifestyle-limiting symptoms should undergo both a supervised exercise program and pharmacologic therapy for symptom relief, in addition to antiplatelet therapy with or without antithrombotic therapy (aspirin alone, or clopidogrel alone, or low-dose rivaroxaban combined with low-dose aspirin in selected patients with low bleeding risk).[2]

Exercise therapy has been shown in multiple studies (but of limited quality) to improve walking time and relieve symptoms.[30][59] [ ]

A supervised exercise training program consists of 30-45 minutes per session, 3 times a week for 12 weeks. If supervised exercise therapy is not feasible, community-based walking programs have also shown some benefit.[60]

Symptom relief can be achieved with cilostazol.[2][61] Cilostazol may improve pain-free walking distance in patients with intermittent claudication. However, participants taking cilostazol had higher odds of experiencing headache.[62][63] One meta-analysis demonstrated that the addition of cilostazol to antiplatelet therapy after peripheral vascular interventions is associated with a reduced risk of restenosis, amputation, and target lesion revascularization.[64] Cilostazol also reduces angiographic restenosis after percutaneous transluminal angioplasty and stenting for femoropopliteal lesions.[65] Cilostazol is contraindicated in patients with heart failure of any severity. Patients taking cilostazol should be assessed for benefit 3 months after starting treatment, and treatment ceased if there is not a clinically-relevant improvement in walking distance.

If there is clinical improvement with an exercise program and medication, follow-up visits are recommended. However, if there is no improvement, patients should be referred to a vascular specialist and have their anatomy defined and assessed for revascularization. One Cochrane review found that revascularization does not provide significant benefits compared with exercise therapy alone in terms of functional performance or quality of life; however, revascularization in combination with a conservative therapy of supervised exercise or pharmacotherapy may result in greater improvements compared with conservative therapy alone.[66][67] Intervention for claudication should be carefully considered, as there is potential for complication from any procedure, and the natural history of claudication is not aggressive.

Some patients choose to take a herbal supplement (L-arginine, propionyl L-carnitine, ginkgo biloba). However, the clinical benefit of these supplements is not established.[68][69] [ ]

Chronic limb-threatening ischemia (CLTI)

These patients have symptoms such as ischemic rest pain, gangrene, or nonhealing wounds/foot and leg ulcers; symptoms are present for more than 2 weeks.[2] For these patients, ischemic etiology must be established urgently by physical exam and vascular studies. If patients have documented PAD, they should be immediately referred to a vascular specialist for revascularization.

Risk stratification may be considered based on the Wound, Ischemia, and Foot Infection (WiFi) score.[50]

Patients who have been able to walk before the episode of critical limb ischemia, have a life expectancy of >1 year, and are able to withstand surgery may be candidates for revascularization.

In patients with inoperable chronic critical limb ischemia facing amputation of the leg, spinal cord stimulation may be a helpful treatment option in addition to standard conservative treatment. There is evidence that spinal cord stimulation is associated with higher rates of limb salvage and more prominent pain relief compared with standard conservative treatment alone.[70] [ ] There may be some trial evidence for autologous bone marrow stem cell transplantation as an option for patients with critical limb ischemia.[71] However, other studies have failed to show benefit.[72]

If the patient is not a candidate for revascularization, they should be assessed for amputation where necessary and be on appropriate risk factor reduction medication.

Revascularization referral

The following patients should be referred to a vascular specialist to have their anatomy defined and assessed:

Patients with lifestyle-limiting claudication who continue to have limiting symptoms despite exercise and medication
Patients with critical limb ischemia symptoms (ischemic rest pain, gangrene, nonhealing wounds/foot ulcers)
Patients with acute limb ischemia (sudden decrease in limb perfusion with threatened tissue viability)

Revascularization is recommended if patients have lifestyle-limiting claudication, and have failed to achieve benefit from medications combined with an exercise program. Endovascular and surgical procedures should not be performed in patients with PAD solely to prevent progression to chronic limb ischemia.[2]

Endovascular or surgical revascularization

Endovascular techniques include percutaneous transluminal angioplasty with balloon dilation, stents, atherectomy, laser, cutting balloons, and drug-coated balloons.[73][74] [ ]

For aortoiliac disease, endovascular revascularization is frequently the first choice with surgery reserved for extensive obstructions and lesions treated unsuccessfully with an endovascular procedure, but individual patient factors including treatment preferences should inform the selection of revascularization technique.[1][2]

Surgical endarterectomy or a hybrid approach (surgical and endovascular procedures in combination) is frequently performed for common femoral artery lesions.[1][2] Common femoral endarterectomy has a high patency rate but may be associated with significant complications.[75]

For femoropopliteal artery stenosis, endovascular therapy is frequently performed but surgical endarterectomy is reasonable if perioperative risk is acceptable and technical factors suggest advantages over endovascular approaches.[1][2]

For infrapopliteal artery lesions, endovascular treatment has been limited to threatened limb loss only, but evidence to support either surgical or endovascular approaches is lacking.[2] Surgical revascularization to tibial targets has a primary patency at 1, 3, and 5 years of 66%, 59%, and 55%, respectively.[76]

Regardless of the procedure selected, all patients undergoing surgical or endovascular revascularization should receive lifelong aspirin treatment.[1][77] There is evidence to support the addition of low-dose rivaroxaban to aspirin post-revascularization (endovascular and surgical), but this combination is associated with a higher risk of major bleeding compared with aspirin alone.[2][78][79]

Current evidence has not yet established whether bypass surgery or endovascular intervention is superior for initial treatment for critical limb ischemia, although many operators have adopted an "endovascular first" strategy.[80][81] Care must be individualized to the patient.

Considerations for common comorbidities and risk enhancers

The presence of specific comorbidities and risk factors increases the risk for major adverse cardiovascular events and major adverse limb events in those with PAD. Multisociety US guidelines recommend that patients with PAD should be assessed for these risk amplifiers when developing patient-focused treatment recommendations.[2]

Hypertension
Dyslipidemia
Diabetes
CKD/end-stage renal disease
Depression
Atherosclerotic disease in more than one vascular bed (PAD, coronary artery disease, cerebrovascular disease)
Microvascular disease (retinopathy, neuropathy, nephropathy)
Current smoking/tobacco use
Older age and geriatric syndromes (frailty, mobility impairment, sarcopenia, malnutrition)

Decisions on revascularization approach (surgical vs. endovascular) and assessment for amputation will be affected by the presence of comorbidities and risk amplifiers.[2] Coordination of care across multispeciality teams is important for management of these patients.

Recommendations for managing specific comorbidities

Hypertension

Antihypertensive therapy is recommended in patients with PAD and hypertension to reduce risk of major adverse cardiovascular events.
Multisociety US guidelines recommend a target blood pressure of <130/80 mmHg in those with PAD and hypertension.[2] European Society of Cardiology guidelines recommend a target systolic blood pressure of 120-129 mmHg, if tolerated.[1]
No one class of antihypertensive medication or strategy is superior for lowering blood pressure in patients with PAD; however, ACE inhibitors or angiotensin-II receptor antagonists have been shown to reduce risk of cardiovascular events and are generally preferred.[1][2]

Dyslipidemia

Lipid-lowering therapy with high-intensity statin therapy is recommended in all patients with PAD to reduce major adverse cardiovascular events and major adverse limb events. Multisociety US guidelines recommend a target low-density lipoprotein cholesterol (LDL-C) level of <70 mg/dL.[2] European Society of Cardiology guidelines recommend a target of <55 mg/dL.[1]
In those with PAD on maximally tolerated statin therapy and with LDL-C below target, additional lipid-lowering therapy with ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor may be considered.[1][2]
For patients who have high-risk PAD and elevated triglycerides despite lifestyle changes and statin therapy, European Society of Cardiology guidelines provide a weak recommendation for the addition of icosapent ethyl.[1] The US National Lipid Association also recommends addition of icosapent ethyl for patients ages 45 years or older with established atherosclerotic cardiovascular disease and elevated triglycerides who are already on high-intensity or maximally tolerated statin therapy.[82]

Diabetes

Patients with diabetes are at an increased risk of PAD progression and have an increased risk of major adverse cardiovascular events and major adverse limb events. A guideline-based program of pharmacologic and nonpharmacologic therapies for patients with diabetes and PAD is recommended, including glycemic control, foot care and ulcer prevention, management of diet and weight, and control of cardiovascular risk factors.[2] Glycemic control may improve limb outcomes.[2]
In those with PAD and type 2 diabetes mellitus, glycemic control with a glucagon-like peptide-1 (GLP-1) receptor agonist (e.g., liraglutide, semaglutide) and/or a sodium-glucose cotransporter-2 (SGLT2) inhibitor (e.g., canagliflozin, dapagliflozin, empagliflozin) may be preferred, as they have been shown to reduce the risk of major adverse cardiovascular events.[1][2]
Coordination of care is essential in patients with diabetes and PAD.[2]

Chronic kidney disease (CKD)

The presence of comorbid CKD in patients with PAD increases the risk of major adverse cardiovascular events and major adverse limb events. Those with end-stage renal disease are at higher risk of lower extremity amputation and readmission after revascularization.[2] In those being considered for revascularization, an endovascular approach may be preferred over a surgical approach.
Some drugs should be used with caution in patients with renal impairment and a dose adjustment may be required. Some drugs may also be contraindicated in patients with renal impairment. Check your local drug information source for more information.

Depression

Depression and other mental health issues such as anxiety and stress are common comorbidities in those with PAD.[2]
The presence of depressive symptoms has been associated with an increased risk of major adverse cardiovascular events and major adverse limb events in patients with PAD; screening for depression is recommended.[2]

Coronary artery disease (CAD)

The same risk factors that predispose to coronary disease increase the risk of PAD. Measures taken to treat coronary disease may also benefit patients with PAD.
CAD is an important comorbidity; it is a similar disease process to PAD in a different vascular bed. Patients with PAD and CAD have a high risk of major adverse cardiovascular events; screening for coronary disease is recommended, with optimization of medical therapy.[1][2] Management of PAD is not generally altered in the presence of chronic coronary disease.
See Chronic coronary disease.

Atrial fibrillation (AF)

In patients with PAD and AF, long-term anticoagulant therapy is recommended for reduction of ischemic stroke and other ischemic events.[83] Oral anticoagulant monotherapy (preferably with a DOAC) without use of an antiplatelet agent is recommended for many patients with stable PAD.[1][83]
In patients with PAD and AF who are undergoing revascularization (endovascular or surgical), addition of a single antiplatelet agent (clopidogrel is preferred) to long-term oral anticoagulation may be considered temporarily (1-3 months), taking bleeding risk into account.[1][83][84]Kumbhani DJ, Cannon CP, Beavers CJ, et al. 2020 ACC expert consensus decision pathway for anticoagulant and antiplatelet therapy in patients with atrial fibrillation or venous thromboembolism undergoing percutaneous coronary intervention or with atherosclerotic cardiovascular disease: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021 Feb 9;77(5):629-58.
See Established atrial fibrillation.

Heart failure

Patients with PAD and comorbid heart failure have an increased risk of major adverse cardiovascular events and all-cause mortality.
European Society of Cardiology guidelines note that evaluation of left ventricular function in those with PAD may be useful for cardiovascular risk stratification and disease management, which may be important when an intermediate- or high-risk vascular intervention is planned.[1]
Cilostazol is contraindicated in patients with heart failure of any severity.

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